Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

METHODOLOGICAL CONSIDERATIONS
IN EVALUATING THE Evidence
I he U S Environmental Protection Agency (EPA) charged
the committee responsible for this report with two primary
objectives:
1. To provide the scientific and technical basis for communi-
cations to the public on
asthma; and
lutants.
· the health impacts of indoor pollutants related to
· mitigation and prevention strategies to reduce these pol
2. To help determine what research is needed in these areas.
To help operationalize the first objective, EPA posed several
questions for the committee's consideration. The committee was
asked to evaluate the strength of the scientific evidence associat-
ing exposure to indoor pollutants with asthma, to discuss what
was known about how and in what way~s) various pollutants in-
fluence asthma, and to examine the risk for development or exac-
erbation of asthma associated with indoor exposures.
EPA asked for information on the characteristics of the indi-
viduals most at risk for these exposures and on the role of genetic
39

40
CLEARING THE AIR
and other environmental factors in the occurrence of asthma. It
requested information about whether effective strategies to miti-
gate or prevent problematic exposures had been developed and
tested, whether these strategies had been shown to decrease
asthma as well, at what exposure levels such decreases had been
shown to occur, and whether the strategies were reasonable and
cost-effective for affected individuals to undertake.
The ensuing chapters of the report address these questions, to
the extent permitted by currently available science. They also
touch on issues identified by the committee as relevant to its
charge.
EVALUATING THE EVIDENCE
The evaluation of evidence involves several stages: (1) assess-
ing the quality and relevance of individual reports; (2) deciding
on the possible influence of error, bias, or confounding on the
reported results; (3) integrating the overall evidence within and
across diverse areas of research; and (4) formulating the conclu-
sions themselves. These aspects of a review require thoughtful
consideration of both quantitative and qualitative information-
they cannot be accomplished by adherence to a prescribed for-
mula.
The approach applied by the committee to this task evolved
throughout the process of review and was determined in impor-
tant respects by the nature of the evidence, exposures, and out-
comes at issue. Ultimately, the conclusions expressed in this re-
port are based on the committee's collective judgment. The
committee endeavored to express its judgments as clearly and
precisely as the available information allowed.
This section describes more fully how the evidence was evalu-
ated. It discusses the research approach used to develop informa-
tion, the methodologic considerations underlying the evaluation,
considerations in assessing the strength of the evidence, and the
categories of evidence used to summarize the committee's con-
clusions. The section is based on similar discussions in the Insti-
tute of Medicine (IOM) reports characterizing scientific evidence
regarding vaccine safety (IOM, 1991, 1993) and the health effects
of herbicides used in Vietnam (IOM, 1994, 1996, 1999), adapted to
the current task.

METHODOLOGICAL CONSIDERATIONS
41
Research Approach
To answer the questions posed by the EPA, the committee
undertook a wide-ranging evaluation of the research on asthma
and indoor air. While it did not review all such literature an un-
dertaking beyond the scope of this report the committee at-
tempted to cover the work it believed to be influential in shaping
scientific understanding at the time it completed its task in mid
1999.
The committee consulted several sources of information in
the course of its work. For conclusions regarding asthma out-
comes, the primary source was epidemiologic studies. Most of
these studies examined general population exposures to indoor
agents at home, reflecting the focus of researchers working in this
field. A small number of studies of occupationally exposed indi-
viduals were also evaluated. Some clinical research for example,
that addressing challenge tests and animal studies were consid-
ered where appropriate. Engineering, architecture, and physical
sciences literature informed the discussions of building charac-
teristics, exposure assessment and characterization, indoor damp-
ness, pollutant transport, and related topics; public health and
behavioral sciences research was consulted for data on the effec-
tiveness of interventions to limit exposure to problematic indoor
agents. The committee also benefited from presentations of cut-
ting-edge research given during two workshops it held in early
1999. A listing of the participating researchers and their topics is
given in Appendix B.
The committee attempted to fairly consider and weigh all rel-
evant information in reaching its conclusions. The failure to cite a
particular study or research effort, however, does not necessarily
mean that the committee did not consider its results.
Methodologic Considerations in Evaluating the Evidence
Uncertainty and Confidence
All science is characterized by uncertainty. Scientific conclu-
sions concerning the result of a particular analysis or set of analy-
ses can range from highly uncertain to highly confident the
theoretical concept of "proof" does not apply in evaluating actual

42
CLEARING THE AIR
observations. In its review, the committee evaluated the degree of
uncertainty associated with the results on which it had to base its
conclusions.
Statistical significance is a quantitative measure of the extent to
which chance that is, sampling variation might be responsible
for the observed exposure-adverse event association. The magni-
tude of the probability value or the width of the confidence inter-
val associated with an effect measure such as the relative risk or
risk difference is generally used to estimate the role of chance in
producing the observed association. This type of quantitative es-
timation is firmly founded in statistical theory on the basis of re-
peated sampling.
For individual studies, confidence intervals around estimated
results such as relative risks represent a quantitative measure of
uncertainty. Confidence intervals present a range of results that,
with a predetermined level of certainty, is consistent with the ob-
served data. The confidence interval, in other words, presents a
statistically plausible range of possible values for the true relative
risk. When it is possible to use meta-analysis to combine the re-
sults of different studies, a combined estimate of the relative risk
and confidence interval may be obtained.
For an overall judgment about an association between an ex-
posure and a disease outcome based on a whole body of evidence,
no quantitative method exists to characterize the uncertainty of
the conclusions. Thus, to assess the appropriate level of confi-
dence to be placed in the ultimate conclusions, it is useful to con-
sider qualitative as well as quantitative aspects.
Analytic Bias
Analytic bias is a systematic error in the estimate of associa-
tion between the exposure and the adverse event. It can be cat-
egorized under four types: selection bias, information bias, con-
founding bias, and reverse causality bias. Selection bias refers to
the way that the sample of subjects for a study has been selected
(from a source population) and retained. If the subjects in whom
the exposure-adverse event association has been analyzed differ
from the source population in ways linked to both exposure and
development of the adverse event, the resulting estimate of asso-
ciation will be biased. Information bias can result in a bias toward

METHODOLOGICAL CONSIDERATIONS
43
the null hypothesis (no association between the exposure and the
adverse event), particularly when ascertainment of either expo-
sure or outcome has been sloppy, or it may create a bias away
from the null hypothesis through such mechanisms as recall bias
or unequal surveillance in exposed versus unexposed subjects.
Confounding bias addressed in greater detail below occurs
when the exposure-adverse event association is biased as a result
of a third factor that is both capable of causing the adverse event
and is statistically associated with the exposure itself. Finally, re-
verse causality bias can be a concern where it is possible that the
outcome in question might influence the probability of experienc-
ing the exposure being studied. It is not generally possible to
quantify the impact of such nonrandom errors in estimating the
strength of the association.
Confounding
In any epidemiologic study comparing an exposed to an un-
exposed group, it is likely that characteristics other than exposure
may differ between the two groups. For example, the group ex-
posed to a particular indoor pollutant may be of lower socioeco-
nomic status than the unexposed group. When the groups differ
with respect to factors that are also associated with the risk of the
outcome of interest, a simple comparison of the groups may ei-
ther exaggerate or hide the true difference in disease rates that is
due to the exposure of interest. In the example of socioeconomic
status, a simple comparison of asthma rates among the exposed
and unexposed would exaggerate an apparent difference in
asthma rates, since socioeconomic status is also thought to influ-
ence asthma incidence. If exposed individuals were of higher so-
cioeconomic status, the simple comparison would tend to mask
any true association between exposure and asthma by spuriously
elevating the risk of disease in the unexposed group. This phe-
nomenon, known as confounding, represents a major challenge
to researchers and those evaluating their work.
Publication Bias
An important aspect of the quality of a review is the extent to
which all appropriate information is considered and any serious

44
CLEARING THE AIR
omission or inappropriate exclusion of evidence is avoided. A pri-
mary concern in this regard is the phenomenon known as publi-
cation bias. It is well documented (Beg" and Berlin, 1989; Berlin et
al., 1989; Callaham et al., 1998; Dickersin, 1990; Dickersin et al.,
1992; Easterbrook et al., 1991) in the scientific literature that stud-
ies with a statistically significant finding are more likely to be
published than studies with nonsignificant results. Where such
bias is present, evaluations of disease-exposure associations
based solely on published literature could be biased in favor of
showing a positive association. Other forms of bias related to re-
porting and publication of results have also been suggested. These
include multiple publications of positive results, slower publica-
tion of nonsignificant and negative results, and publication of
nonsignificant and negative results in non-English-language and
low-circulation journals (Sutton et al., 1998~. Several researchers
have addressed the specific topic of whether there is bias in the
publication of studies regarding the health impacts of exposure
to environmental tobacco smoke (Berg et al., 1994; Kawachi and
Colditz, 1996; Lee, 1998; Misakian and Bero, 1998~.
The committee did not in general consider the risk of publica-
tion bias to be high among studies of indoor air exposures and
asthma because
1. there were numerous published studies showing no posi-
tive association;
2. the committee was aware of the results of some unpub-
lished research; and
3. The committee felt that the interest of the research commu-
nity, public health professionals, government, and the general
public surrounding the issue of asthma is so intense that any stud-
ies showing no association would be unlikely to be viewed as
unimportant by investigators. In short, there would also be pres-
sure to publish "negative" findings.
Nonetheless, the committee was mindful of the possibility that
studies showing a positive association might be overrepresented
in the published literature.

METHODOLOGICAL CONSIDERATIONS
Considerations in Assessing the Strength of
Scientific Evidence
Causality Definitions
45
The question of causality is of cardinal importance in health
research, clinical practice, and public health policy. Despite its
importance, however, causality is not a concept that is easy to
define or understand (Kramer and Lane, 1992~. Consider, for ex-
ample, the relation between a hypothetical exposure X and
asthma. Does the statement "X causes asthma" mean that (1) all
persons exposed to X will develop asthma, (2) all cases of asthma
are caused by exposure to X, or (3) there is at least one person
whose asthma was caused or will be caused by X?
The first interpretation corresponds to the notion of a suffi-
cient cause; X is a sufficient cause of asthma if all individuals ex-
posed to X develop the disease. X is a necessary cause of asthma if
the disease occurs only among those exposed to X, the second
interpretation above. The idea that a "proper" cause must be both
necessary and sufficient underlies the postulates of causality ar-
ticulated by Koch in the 1800s (Susser, 1973~. However, it is now
generally recognized that for most exposure-outcome relations, a
particular exposure need not be necessary or sufficient in order to
cause the outcome the third interpretation above. In other
words, most health outcomes of interest have multifactorial eti-
ologies.
This third form of causality is what is meant when scientists
say that cigarette smoking causes lung cancer. Not everyone who
smokes will develop lung cancer and not everyone who develops
Jung cancer smokes. However, individuals who smoke are more
likely to develop Jung cancer than those who do not, and the more
they smoke the more likely they are to develop it.
Types of Causal Questions
The causal relation between an exposure and a given adverse
event can be considered in terms of three different questions
(Kramer and Lane, 1992~:

46
CLEARING THE AIR
1. Can It? (potential causality): Can the exposure cause the
adverse event, at least in certain people under certain circum-
stances?
2. Did It? (retrodictive causality): Given that an individual
who was subjected to the exposure developed the adverse event,
was the event caused by the exposure?
3. Will It? (predictive causality): Will the next person who is
subjected to the exposure experience the adverse event because
of the exposure? Equivalently, how frequently will those subjected
to the exposure experience the adverse event as a result of the
exposure?
The form of causality relevant to this report is the first of
these potential or "can it?" causality. In the section below, this
form of causality is discussed with reference to how it relates to
the committee's charges and how the committee attempted to an-
swer it.
Evaluation Criteria
Much of the epidemiologic literature on causality has focused
on potential causality, and a widely used set of criteria has
evolved for its assessment (Bradford Hill, 1965; Bradford Hill and
Hill, 1991; Susser, 1973; U.S. Public Health Service, 1964~. These
criteria are also often used to inform public health policy recom-
mendations and decisions (Weed, 1997~.
For each indoor air exposure for which evidence indicated
the presence of an association with asthma, the committee as-
sessed the applicability of each of five general considerations,
based on these criteria:
1. Strength of Association: Strength of association is usually ex-
pressed in epidemiologic studies as the magnitude of the mea-
sure of effect, for example, relative risk or odds ratio. Generally,
the higher the relative risk, the greater is the likelihood that the
exposure-disease association is "real" or, in other words, the less
likely it is to be due to undetected error, bias, or confounding.
Small increases in relative risk that are consistent across a number
of studies, however, may also provide evidence of an association.

METHODOLOGICAL CONSIDERATIONS
47
2. Biologic Gradient (Dose-Response Relationship): In general,
potential causality is strengthened by evidence that the risk of
occurrence of an outcome increases with higher doses or frequen-
cies of exposure. In the case of asthma, however, this is compli-
cated by the central roles that susceptibility and sensitization play
in the disease. The same exposure may have very different effects
in susceptible and nonsusceptible, sensitized and nonsensitized
individuals. Thus, the absence of a dose-response effect might
not constitute strong evidence against a causal relation.
3. Consistency of Association: Consistency of association re-
quires that an association be found regularly in a variety of stud-
ies, for example, in more than one study population and with
different study methods. The committee considered findings that
were consistent across different categories of studies as being sup-
portive of an association. Note that the committee did not inter-
pret "consistency" to mean that one should expect to see exactly
the same magnitude of association in different populations.
Rather, consistency of a positive association was taken to mean
that the results of most studies were positive and that the differ-
ences in measured effects were within the range expected on the
basis of all types of error including sampling, selection bias,
misclassification, confounding, and differences in actual exposure
levels.
4. Biologic Plausibility and Coherence: Biologic plausibility is
based on whether a possible association fits existing biologic or
medical knowledge. The existence of a possible mechanism in-
creases the likelihood that the exposure-disease association in a
particular study reflects a true association. In addition, the com-
mittee considered factors such as evidence in humans of an asso-
ciation between the exposure in question and diseases known
to have causal mechanisms similar to asthma and evidence
that asthma outcomes are associated with occupational exposure
levels.
Considerations of biologic plausibility informed the com-
mittee's decisions about how to categorize the association be-
tween various indoor exposures and asthma, but the committee
.
recognized that research regarding mechanisms is still in its in-
fancy and did not predicate decisions on the existence of specific

48
CLEARING THE AIR
evidence regarding biological plausibility. Chapter 4 addresses
the state of the science on asthma mechanisms.
5. Temporally Correct Association: If an observed association is
real, exposure must precede the onset or exacerbation of the dis-
ease by at least the duration of disease induction. Temporality
can be difficult to evaluate for some indoor agents because expo-
sure to them is recurrent and pervasive. If individuals are exposed
to an agent almost every day and in an environment where they
spend most of their time it can be difficult to discern a relation-
ship between exposure and effect. The lack of an appropriate time
sequence is thus evidence against association, but the lack of
knowledge about the natural history and pathogenesis of asthma
limits the utility of this consideration. The committee also consid-
ered whether the outcome being studied occurred within a time
interval following exposure that was consistent with current un-
derstanding of its natural history.
Other Considerations As noted above, it is important also to
consider whether alternative explanations error, bias, confound-
ing, or chance might account for the finding of an association. If
an association could be sufficiently explained by one or more of
these alternate considerations, there would be no need to invoke
the several considerations listed above. Because these alternative
explanations can rarely be excluded sufficiently, however, assess-
ment of the applicable considerations listed above almost invari-
ably remains appropriate. The final judgment is then a balance
between the strength of support for the association and the de-
gree of exclusion of alternatives.
SUMMARIZING CONCLUSIONS REGARDING THE EVIDENCE
Categories of Association
The committee summarized its conclusions using a common
format, described below, categorizing the strength of the scien-
tific evidence in two areas:
1. health effects: the association between exposure to an indoor
agent and asthma development or exacerbation; and

METHODOLOGICAL CONSIDERATIONS
49
2. exposure reduction strategies: the effectiveness of exposure
mitigation and prevention measures.
The five categories described below were adapted by the
committee from those used by the International Agency for Re-
search on Cancer (IARC, 1977) to summarize the scientific evi-
dence for the carcinogenicity of various agents. Similar sets of
categories have been used in National Academies' reports char-
acterizing scientific evidence regarding vaccine safety (IOM,
1991, 1993) and the health effects of herbicides used in Vietnam
(IOM, 1994, 1996, 1999~. The distinctions reflect the committee's
judgment that an association would be found in a large, well-
designed study of the outcome in question in which exposure
was sufficiently high, well characterized, and appropriately mea-
sured on an individual basis.
For health effects, the categories relate to the association be-
tween exposure to the agent and asthma, not to the likelihood
that any individual's health problem is associated with or caused
by the exposure.
Each of the categories describes the strength of the scientific
evidence regarding the relationship between an action and an out-
come related to indoor exposures and asthma. Table 2-1 gives ex-
amples of these.
Sufficient Evidence of a Causal Relationship
Evidence is sufficient to conclude that a causal relationship
exists between the action or agent and the outcome. That is, the
TABLE 2-1 Examples of Actions and Outcomes Usecl in Categories of
Eviclence
Category Action Outcome
Exposure reduction
strategies
Health effects Exposu re to an indoor
agent
Implementation of a strategy
to avoid or reduce
exposure to an indoor agent
Asthma development or
exacerbation
Actual reduction of
exposure or reduction of
asthma incidence

50
CLEARING THE AIR
evidence fulfills the criteria below for sufficient evidence of an
association and, in addition, satisfies criteria used to assess cau-
sality:
· Strength of Association: Is the exposure or action associated
with a high probability of the outcome?
· Biologic Gradient (Dose-Response Effect): Is increased expo-
sure to the possible cause associated with increased response? For
consideration of exposure reduction strategies, does more effec-
tive implementation of the remediation strategy result in a greater
reduction in exposure or in asthma incidence?
· Consistency of Association: Have similar results been ob-
served in multiple studies?
· Biologic Plausibility and Coherence: Is there a reasonable pos-
tulated biologic mechanism linking the possible cause and the
effect?
· Temporally Correct Association: Does the presumed cause
plausibly precede the effect?
These criteria have been discussed in greater detail above.
The finding of sufficient evidence of a causal relationship be-
tween an exposure and an asthma outcome (development or ex-
acerbation) does not mean that the exposure inevitably leads to
that outcome. Rather it means that the exposure can cause the
outcome, at least in certain people under certain circumstances.
Sufficient Evidence of an Association
Evidence is sufficient to conclude that there is an association.
That is, an association between the action or agent and the out-
come has been observed in studies in which chance, bias, and
confounding could be ruled out with reasonable confidence. For
example, if several small studies that are free from bias and con-
founding show an association that is consistent in magnitude and
direction, there may be sufficient evidence of an association.
Limited or Suggestive Evidence of an Association
Evidence is suggestive of an association between the action or

METHODOLOGICAL CONSIDERATIONS
51
agent and the outcome but is limited because chance, bias, and
confounding could not be ruled out with confidence. For example,
at least one high-quality study shows a positive association, but
the results of other studies are inconsistent.
Inadequate or Insufficient Evidence to Determine Whether or
Not an Association Exists
The available studies are of insufficient quality, consistency,
or statistical power to permit a conclusion regarding the pres-
ence or absence of an association; or no studies exist that exam
ine the relationship. For example, available studies may have
failed to control for confounding or may have inadequate expo
sure assessment.
Limited or Suggestive Evidence of No Association
Several adequate studies are mutually consistent in not show-
ing an association between the action or agent and the outcome.
A conclusion of "no association" is inevitably limited to the con-
ditions, level of exposure, and length of observation covered by
the available studies. In addition, the possibility of a very small eleva-
tion in risk at the levels of exposure studied can never be excluded.
ASSESSING EXPOSURES TO AGENTS IN INDOOR AIR
Assessments of exposure to environmental agents in indoor
air play a central role in epidemiology studies seeking to charac-
terize population risks, in screening studies aimed at identifying
individuals at risk, and in interventions designed to reduce risk.
Because of the central importance of exposure assessment, it is
important to understand the strengths and limitations of the ap-
proaches that are available to assess exposures in these contexts.
Definitions of Exposure
Exposure has been defined in various ways in the past. For
example, an Institute of Medicine report (IOM, 1994) defines ex

52
CLEARING THE AIR
posure as "the concentration of an agent in the environment in
close proximity to a study subject."
The National Research Council report Human Exposure Assess-
mentfor Airborne Pollutants (NRC, 1991) adds the concept of time
to that of concentration:
An exposure to a contaminant is defined as an event that occurs
when there is contact at a boundary between a human and the en
vironment with a contaminant of a specific concentration for an
interval of time.
For the purposes of this report, it is convenient to distinguish
between two classes of exposure measures: 1) the theoretically
ideal (and typically unknown) risk-relevant exposure metric (ERR)
that represents the individual breathing zone concentration of an
agent of interest over a time period that is relevant to the risk of
developing the health outcome of interest; and 2) the practical
and available exposure surrogate that correlates to a greater or les-
sor extent with the ERR. The ERR will differ depending on the
health outcome under study (e.g., asthma development versus
asthma exacerbation). An exposure surrogate is any available
measure of exposure that is positively correlated with the ERR.
Better surrogates are those with higher correlations, and thus
lower degrees of exposure misclassification. When used without
qualification in this report, the term "exposure" refers to surro
gate exposure measures.
The ERR is that theoretical measure of exposure that best rep-
resents the risk of adverse health consequences. Researchers don't
know enough about asthma pathogenesis to confidently identify
the appropriate ERR. One possible ERR for development of asthma
might be a long-term average of agent concentration in the breath-
ing zone of the person at risk with duration on the order of 6
months to 2 years measured during a relevant period of Jung or
immune system development, such as during the early years of
life. For this ERR it would seem reasonable to assume that, to a
first order approximation, the average exposure level best repre-
sents risk; however second order effects might relate to variation
around the mean. In the case of asthma exacerbations, the ERR
might be a short-term average that captures peak agent exposures
in the breathing zone immediately prior to the exacerbation. Rel

METHODOLOGICAL CONSIDERATIONS
53
event averaging times might range from approximately 20 min-
utes to 48 hours.
In this context, the quality of any particular exposure surro-
gate measure can be judged in terms of how close it comes (i.e.,
correlates) to the ERR in terms of the following four components:
life?
1. Does it represent the key agent; that is, the agent solely or
primarily responsible for the outcome?
2. Does it represent breathing-zone concentration?
3. Does it average appropriately over time?
4. Does it capture exposure during the vulnerable period of
A wide range of exposure surrogates exists. Figure 2-1 sum-
marizes the principal approaches that are available for develop-
ing exposure surrogates (adapted from NRC, 1991~.
Direct exposure surrogates include personal monitoring in-
volving the measurement of agent concentrations using monitors
carried by individual subjects, and biological markers involv-
ing the measurement of the agent or its metabolite in biological
samples such as urine and blood. These offer more proximal mea-
sures of individual exposure than do the indirect approaches,
though usually at the expense of sample size or ability to charac-
terize long-term exposures. Indirect measures include environ-
mental area monitoring (e.g., room sampling), models (e.g., mi-
croenvironmental model), recall questionnaires and real-time
diaries. These approaches tend to be more practical in large-scale
Exposure Assessment
Approaches
Direct Methods
Personal
Monitoring
| indirect Methods |
Biological
Markers
Environmen; | Models
|Monitoring
| Questionnaires | | Diaries
FIGURE 2-1. Classification of surrogate exposure assessment approaches.
SOURCE: adapted from NRC (1991~.

54
CLEARING THE AIR
studies, and often are better suited to long-term exposure charac-
terization than are direct measures.
The Microenvironmental Model
The microenvironmental mode] of total human exposure is a
widely accepted too] for environmental exposure assessment
(Sexton and Ryan, 1988~. In this model, exposure of an individual
to an airborne agent is defined as the time-weighted average of
agent concentrations encountered as the individual passes
through a series of microenvironments:
Ei = ~ Cjti; ~
where Ei is the time-weighted integrated exposure for person i
over the specified time period; Cj is the is concentration of agent
in microenvironment j; tij is the amount of time person i spent in
microenvironment j, and ~ is the total number of microenviron-
ments that person i moves through during the specified time pe-
riod (24 hours, for example).
Sexton and Ryan (1988) define a microenvironment as "a 3-
dimensional space with a volume in which contaminant concen-
tration is spatially uniform during some specific interval." Ex-
amples include homes, offices, schools, and vehicles. An
additional key assumption that is usually made is that the mi-
croenvironmental concentration is independent of time. These
assumptions underlie the many attempts to use this mode] to re-
construct personal exposures to airborne contaminants based on
environmental monitoring of microenvironments along with as-
sessment of time-activity patterns. Unfortunately, the space and
time continuity assumptions are rarely met in practice, severely
limiting the utility of the microenvironmental modeling approach
for estimating personal exposures. This is also likely to be the
case for many of the indoor agents with plausible roles in asthma,
such as particulate allergens. Exposures to such agents occur epi-
sodically due to the inadvertent disturbance and resuspension of
allergen reservoirs by individual activities. These episodic expo-
sure patterns are not likely to be accurately captured by environ

METHODOLOGICAL CONSIDERATIONS
55
mental area samplers. Possible exceptions include ETS and air-
borne cat allergen, for which within-Iocation spatial and tempo-
ral variations appear to be less pronounced (Samet, 1999; Chew et
al., 1999~.
Dose Concepts
.
Individual ex gosure to an airborne agent results in inhalation
of the agent and deposition in the lungs. Dose is the amount of an
agent that is absorbed or deposited in the body of an exposed
organism for an increment of time (NRC, 1991~. The NRC report
further distinguishes between internal dose and biologically effec-
tive dose. Internal dose is defined as the amount of an agent that is
absorbed into the body over a given time whereas biologically
effective dose is the amount of an agent or its metabolites that has
interacted with a target site over a given period of time.
For inhaled gases, the primary determinant of the lung depo-
sition fraction (the proportion of inhaled mass that is deposited in
the lungs) and the pattern of deposition in the lungs is the solu-
bility of the gas. The primary determinant of deposition for par-
ticles is the aerodynamic particle diameter (dae). Aerodynamic
particle diameter, as distinct from physical diameter, determines
the motion of particles in air. The dae of a particle is defined as the
diameter of the unit density sphere that has the same terminal
settling velocity as the particle of interest (ICRP, 1994~. Particles
with dae larger than 15 ,um are captured preferentially (though
not exclusively) in the upper respiratory tract (i.e., nose and
throat). Particles with dae between 2.5 and 15 ,um enter the lungs
but tend to deposit in the upper conducting airways where their
mass and the high velocities favor inertial impaction. Because
they lack inertia, smaller particles move with the inhaled air-
stream into the alveolar region, where they may or may not de-
posit. Deposition fraction in the deep lung increases with decreas-
ing dae below 0.5 sum due to the high diffusion constants of very
small particles.
The role of particle density in determining dae is critical. A
spherical particle with a physical diameter of 16 ,um but with a
density of 0.1 will behave aerodynamically like a 5 ,um water
droplet. This property helps to explain the ability of large-diam

56
CLEARING THE AIR
eter, low-density pollen grains to penetrate and deposit in the
Jung. Once deposited in the lungs, airborne agents may react with
biomolecules, be absorbed into the blood, or be cleared from the
lungs. From the viewpoint of asthma development or exacerba-
tion, the relevant sites and nature of interactions between inhaled
agents and human body remain uncertain, limiting our ability to
define biologically effective dose in this context. In the case of
allergens, however, the measurements of serum IgE and allergen
skin test reactivity represent surrogates for biologically effective
dose. It is important to note that all measures of dose, like those of
exposure, can be viewed as surrogates for the theoretical risk-rel-
evant dose measure.
Exposure Assessment for Specific Agents
Considered in This Report
Table 2-2 lists the exposure and dose surrogates that have been
used in past studies of agents with possible links to asthma devel-
opment or exacerbation. The text that follows addresses issues
related to assessing exposures to some of the agents addressed in
this report. More detailed information on these agents and others
evaluated in the report is given in Chapters 5 through 10.
House dust mite (HDM) exposure is associated primarily
with inhalation of mite fecal pellets and aggregates (Chapman
and Platts-MilIs, 1980; Tovey et al., 1981~. Most allergen-related
particles are in the size range from 10-25 ,um and are thought to
become airborne primarily via active disturbance of allergen res-
ervoirs in beds, soft furniture, and carpets (Tovey et al., 1981~.
Because of their large size, HDM allergen-related particles remain
airborne for relatively short time periods (on the order of min-
utes). As such, area sampling of air concentrations has not proven
a useful method of exposure assessment. Personal sampling is
theoretically possible but requires further development. The cur-
rently accepted method for routine characterization of HDM ex-
posures is to assay concentrations of group 1 allergens in dust
samples collected by vacuuming, preferably in the bed or bed-
room. Allergen concentrations are usually expressed in units of
,ug HDM/gram of dust collected. A theoretical advantage of
dustborne allergen sampling is the presumed time-integration

58
CLEARING THE AIR
that occurs in the deposition of allergen particles on surfaces over
time.
It is worth noting one limitation of the common practice of
reporting concentrations of allergen in settled dust samples in
units of mass of allergen per gram of dust collected. By dividing
by total dust collected, this expression of exposure does a poor
job of characterizing the total allergen burden in a dwelling. For
example, two homes A and B could have the same amount of
allergen per gram of house dust by the conventional measure,
whereas home A might have 10 times more house dust than home
B. resulting in a 10-fold higher average exposure to occupants of
home A. A high priority research need is the development of im-
proved sampling methods that enable better standardization for
area sampled than is possible using current methods.
Like HDM, cockroach allergens are thought to be associated
primarily with larger particles that become airborne during and
immediately after active disturbance of dust reservoirs. Thus, the
same measurement issues apply here as for HDM. In contrast to
HDM, which thrive primarily in bed, furniture and carpet materi-
als, cockroach populations are usually concentrated in kitchens
and bathrooms due to the availability of water and food sources.
As a result, dust concentrations of cockroach allergen (,ug/g) are
often an order of magnitude higher in kitchen samples than in
bedrooms (Sarpong et al., 1996~. Even so, bedroom concentrations
are generally thought to represent a better measure of human ex-
posure to cockroach allergen for most individuals, due both to
the duration of time spent in the bedroom and the likelihood of
allergen disturbance there (Eggleston et al., 1998; Rosenstreich et
al., 1997~. For very young children who craw! or toddle on the
floor, dustborne cockroach allergen on floors throughout the
home may be relevant to exposures.
The principal cat allergen Fe! `1 I is produced by salivary, seba-
ceous, and anal glands (De Andrade et al., 1996~. Fe! ~ I can be
quantified in dust and air samples and also by specific IgE. A
significant portion of airborne Fe! ~ I is associated with particles
less than 5 ,um dae which remain airborne for extended periods
and therefore tend to be distributed widely within interior spaces
(Custovic et al., 1998~. Fe! ~ I also can be transported between
locations via adherence to and resuspension from clothing, lead

METHODOLOGICAL CONSIDERATIONS
59
ing to measurable concentrations not only in homes with cats but
also in schools, offices, vehicles, and homes with no cats. Because
of this, home-based Fe! ~ I concentrations often represent only
one component of total human exposure. Dog and other animal
allergen exposures have been studied less extensively; however,
the basic parameters of exposure appear to be similar to those
discussed above for cats (Custovic et al., 1997~.
While several methods currently exist for measuring and
characterizing fungal populations, methods for assessing human
exposure to fungal allergens remain poorly developed at present,
and represent a high priority research need. Part of the difficulty
relates to the large number of fungal species that are measurable
indoors, and the fact that fungal allergen content varies across
species and across morphological forms within species (Cruz et
al, 1997; Fade! et al., 1992~. In addition, the most common meth-
ods for fungal assessment, counting cultured colonies and the
identification and counting of spores, have variable and uncer-
tain relationships to allergen content. Exposure surrogates based
on questionnaire or inspection such as water damage and vis-
ible fungal growth also have very uncertain relationships with
exposure to airborne fungal allergens. Although it is clear that
individuals can be allergic to fungi, measurements of fungal al-
lergen concentrations are very rarely included in epidemiological
studies.
Indoor concentrations of airborne pollens occur via penetra-
tion of outdoor pollens into interior spaces, rather than emissions
indoors. Penetration efficiency depends primarily on the size and
shape of openings through which air enters the building open
windows versus small cracks, for example and on aerodynamic
particle diameter. Pollen grains often have large physical diam-
eters but relatively small dae due to their low densities, favoring
penetration. This allows pollens to remain airborne for long peri-
ods outdoors and be widely distributed by winds, as well as to
penetrate indoors. Allergens from some plants, such as grass and
birch, are located within particles that are much smaller than pol-
len grains (see Chapter 10~. Indoor concentrations of particles
from outdoors depend on the rate of depositional losses to indoor
surfaces, the building ventilation rate, and the particle penetra-
tion efficiency.

60
CLEARING THE AIR
Environmental tobacco smoke (ETS) is a complex mixture of
submicron particles and gases produced by the combustion of to-
bacco products (Daisey et al., 1994; U.S. EPA, 1992~. ETS remains
airborne for long periods after emission, allowing time for dis-
persion and spread throughout interior spaces. Removal mecha-
nisms include deposition onto interior surfaces and dilution by
building ventilation. Significant ETS concentrations typically oc-
cur only indoors.
Questionnaire-based assessment of indoor smoking patterns
has been used in many studies as an exposure surrogate. An im-
portant advantage of this approach is the potential it offers to cap-
ture long-term average indoor ETS emission patterns, which is
less feasible to do with airborne measurements. A limitation of
questionnaire-based exposure assessment is the potential for dif-
ferential self-reporting of smoking patterns as a function of edu-
cation and cultural attitudes.
Methods now exist for airborne measurements of chemical
markers of the gaseous and particle phases of airborne ETS; how-
ever, the relationship between these marker compounds and the
concentrations of the broader mixture of ETS constituents is still
under investigation. While ETS is a major source of indoor PM2 5
concentrations, PM2 5 iS not specific to ETS. For example, airborne
nicotine concentrations are often used as a specific marker for the
gaseous constituents of ETS. (Samet, 1999~. Nicotine is a semi-
volatile organic component of ETS.
Little data exist on the temporal variability of indoor ETS con-
centrations and it is not known what averaging time is adequate
for characterizing long-term airborne ETS exposure of building
occupants. Personal sampling represents an attractive approach
in terms of sampling location; however, to be valid, the averaging
time must be sufficiently long to estimate the long-term average
exposure. Sampling with area monitors (i.e., nicotine sampler in
bedroom or main activity room) enables more convenient and
extensive sampling of long-term ETS exposures (e.g., over 1-2
weeks duration), and is thus recommended for epidemiology
studies.
Biomarkers of ETS exposure also play an important role in
research on ETS exposure and health. Cotinine, a biological me-
tabolite of nicotine, can be measured in urine, blood, and saliva

METHODOLOGICAL CONSIDERATIONS
61
(Benowitz, 1996~. An important attribute of biomarkers such as
cotinine is that they reflect exposures from all routes and loca-
tions such as cotinine concentration in urine reflects not only
ETS exposure in the home but also at work, in school or daycare,
while shopping, in vehicles, and the like. This may be an advan-
tage or disadvantage depending on the context. A limitation of
cotinine for long-term exposure assessment is its relatively short
biological half-life, on the order of several hours. Thus, cotinine
measurements provide a measure of recent exposure, with sig-
nificant modification by time since last exposure and individual
metabolism rate. Because of these limitations, a single measure-
ment of cotinine in urine or blood provides a good indication of
whether recent exposure has occurred, but is generally not an ac-
curate measure of long-term exposure levels.
Nitrogen dioxide (NO2) is an irritant gas produced by high
temperature combustion. Indoor sources include gas stoves and
unvented space heaters. Indoor NO2 levels are also influenced by
the penetration of outdoor NO2, which is elevated in urban areas
where motor vehicles are the dominant source. Factors that influ-
ence concentrations of indoor NO2 include frequency and dura-
tion of combustion appliance usage, emission rates of individual
appliances, and home ventilation rate (Samet et al., 1987~. High
ventilation rates act to reduce NO2 levels generated indoors, but
conversely to increase penetration of NO2 of outdoor origin.
Available measures of indoor NO2 exposures include question-
naire-based self-reporting of gas appliance presence or usage, en-
vironmental area sampling of airborne NO2 levels, and personal
sampling of airborne NO2 levels. Questionnaire-based assessment
is logistically simple but does not account well for variations in
emission and ventilation rates. The sampling methods inherently
account for these factors, as well has being specific for NO2. How-
ever, as with most sampling methods, area and personal sampling
characterizes only a snapshot in time, which may or may not be a
good surrogate for long-term average indoor NO2 levels.
Given the variety and complexity of indoor volatile organic
compound (VOC) emission sources and rates, there is in general
no reliable method for characterizing indoor VOC levels other
than air sampling. A number of methods exist for both area and
personal sampling of airborne VOCs. Of particular interest are

62
CLEARING THE AIR
recently developed passive diffusion badges that can measure
VOC levels in the ,ug/m3 range with sampling duration of 48
hours or more (Stock et al., 1996~. Internal dose assessment is pos-
sible based on both exhaled breath and blood sampling; however,
both methods address only recent exposures (e.g., within the pre-
vious 24 hours).
OTHER CONSIDERATIONS
The committee did not fee! that there was sufficient evidence
to generate confident quantitative estimates of the asthma risk
associated with indoor air exposures. It is not possible to make
general statements about the relative risk of various exposures
because this is highly dependent on the characteristics of a par-
ticular environment and its occupants. House dust mites, for ex-
ample, are a very common exposure in temperate and humid re-
gions such as the southeastern United States but do not typically
present a problem in cooler and drier climates such as northern
Europe. Cockroaches, which also thrive in temperate and humid
regions, are an important exposure in some urban environments.
Fungi are ubiquitous and can be the primary source of allergen in
some arid climates. Endotoxins may be found in humidifiers in
urban settings or in organic dusts that infiltrate rural homes from
outdoors. Occupant choice has a major role in determining in-
door exposure to animals, plants, environmental tobacco smoke,
indoor combustion sources, and chemicals used in cleaning and
other activities. Indoor chemical exposures also result from out-
door infiltrates and certain building materials and furnishings.
Much of the literature regarding indoor exposures and asthma
outcomes focuses on single agents, and the report thus has this
same focus. Real indoor environments, however, are complex.
They subject occupants to multiple exposures that may interact
physically or chemically with one another and with the other
characteristics of the environment like humidity, temperature,
and ventilation levels. Synergistic effects that is, interactions
among agents that result in a combined effect greater than the
sum of the individual effects may also take place. Information
on the combined effects of multiple exposures and on synergistic

METHODOLOGICAL CONSIDERATIONS
63
effects among agents is cited wherever possible. However, rather
little data are available on this topic and it remains an area of
active research interest.
Exposures in the indoor environment are not the only factor
that may influence asthma outcomes, and interventions that con-
sider only indoor factors may miss important opportunities to
improve health. This report touches on the roles that genetics and
socioeconomic status may play, although these subjects are not
addressed in detail. Research has also examined the possible in-
fluence of several other factors, including antibiotic use (von
Mutius et al., 1999), breastfeeding (Oddy et al., 1999) and other
aspects of diet (Kimber, 1998; Weiss, 1999), low birth weight
(Shaheen et al., 1999), number of siblings (Ponsonby et al., 1999),
and obesity (Luder et al., 1998~.
REFERENCES
Begg CB, Berlin JA. 1989. Publication bias and dissemination of clinical research.
Journal of the National Cancer Institute 81~2~:107-115.
Benowitz NL. 1996. Cotinine as a biomarker of environmental tobacco smoke
exposure. Epidemiologic Reviews 18~2~:188-204.
Berlin JA, Begg CB, Louis TA. 1989. An assessment of publication bias using a
sample of published clinical trials. Journal of the American Statistical
Association 84:381-392.
Bero LA, Glantz SA, Rennie D.1994. Publication bias and public health policy on
environmental tobacco smoke. Journal of the American Medical Association
272~2~:133-136.
Bradford Hill A. 1965. The environment and disease: association or causation.
Proceedings of the Royal Society of Medicine 58:295-300.
Bradford Hill A, Hill ID. 1991. Bradford Hill's Principles of Medical Statistics
(Twelfth Edition). London: Hodder & Stoughton.
Callaham ML, Wears RL, Weber EJ, Barton C, Young G. 1998. Positive-outcome
bias and other limitations in the outcome of research abstracts submitted to a
scientific meeting. Journal of the American Medical Association 280~3~:254-
257. [Published erratum appears in JAMA 1998 280~14~:1232.1
Chapman MD, Platts-Mills TA. 1980. Purification and characterization of the
major allergen from Dermatophagoides pteronyssinus-antigen P1. Journal of
Immunology 125~2~:587-592.
Chew GL, Higgins KM, Gold DR, Muilenberg ML, Burge HA. 1999. Monthly
measurements of indoor allergens and the influence of housing type in a
northeastern US city. Allergy 54~10~:1058-1066.
Cruz A, Saenz de Santamaria M, Martinez J. Martinez A, Guisantes J. Palacios R.

Since about 1980, asthma prevalence and asthma-related hospitalizations and deaths have increased substantially, especially among children. Of particular concern is the high mortality rate among African Americans with asthma.

Recent studies have suggested that indoor exposures--to dust mites, cockroaches, mold, pet dander, tobacco smoke, and other biological and chemical pollutants--may influence the disease course of asthma. To ensure an appropriate response, public health and education officials have sought a science-based assessment of asthma and its relationship to indoor air exposures.

Clearing the Air meets this need. This book examines how indoor pollutants contribute to asthma-- its causation, prevalence, triggering, and severity. The committee discusses asthma among the general population and in sensitive subpopulations including children, low-income individuals, and urban residents. Based on the most current findings, the book also evaluates the scientific basis for mitigating the effects of indoor air pollutants implicated in asthma. The committee identifies priorities for public health policy, public education outreach, preventive intervention, and further research.

Welcome to OpenBook!

You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.